{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:12:28Z","timestamp":1775707948317,"version":"3.50.1"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2018,4,1]],"date-time":"2018-04-01T00:00:00Z","timestamp":1522540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["40-41500-98-9002"],"award-info":[{"award-number":["40-41500-98-9002"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with\n            <jats:italic>a priori<\/jats:italic>\n            birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5\u00b0C), and normal UO (2 ml\/kg\/h), benzylpenicillin CL was 0.48 liter\/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter\/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU\/kg\/day every 8 h (q8h), 150,000 IU\/kg\/day q8h, and 200,000 IU\/kg\/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and \u226542 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.\n          <\/jats:p>","DOI":"10.1128\/aac.02311-17","type":"journal-article","created":{"date-parts":[[2018,1,27]],"date-time":"2018-01-27T11:29:00Z","timestamp":1517052540000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia"],"prefix":"10.1128","volume":"62","author":[{"given":"Yuma A.","family":"Bijleveld","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo R.","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna H.","family":"van der Lee","sequence":"additional","affiliation":[{"name":"Paediatric Clinical Research Office, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Floris","family":"Groenendaal","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands"},{"name":"Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter H.","family":"Dijk","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University of Groningen, Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arno","family":"van Heijst","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogier C. J.","family":"de Jonge","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koen P.","family":"Dijkman","sequence":"additional","affiliation":[{"name":"Department of Neonatology, M\u00e1xima Medical Center Veldhoven, Veldhoven, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrica L. M.","family":"van Straaten","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Isala Clinics, Zwolle, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monique","family":"Rijken","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inge A.","family":"Zonnenberg","sequence":"additional","affiliation":[{"name":"Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Cools","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Vrije Universiteit Brussel, Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Zecic","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University Hospital Gent, Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debbie H. G. M.","family":"Nuytemans","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton H.","family":"van Kaam","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands"},{"name":"Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron A. A.","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"PharmaCool study group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mieke J.","family":"Brouwer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel P.","family":"van den Broek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carin M. 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